Myelin is a fatty white substance that surrounds the axon of some nerve cells, forming an electrically insulating layer. In humans, around 40% of the brain contains white matter comprising densely packed fibers, of which myelin is a main component (50-60% dry weight of the white matter). Myelin is synthesized and maintained by oligodendrocytes (OLs) in the central nervous system (CNS). Oligodendrocytes are a type of neuroglia that function to provide support and insulation to axons in the CNS. Oligodendrocytes are generated from oligodendrocyte precursor cells (OPCs), and are found only in the CNS.
In demyelinating diseases, the myelin sheath of neurons of the nervous system is damaged. This damage may impair the conduction of signals in the affected nerves, leading to, for example, deficiency in sensation, movement, cognition, and other functions, depending on the nerves involved. Among the numerous demyelination diseases, multiple sclerosis (MS) is the most widespread disabling neurological condition of young adults around the world. The Multiple Sclerosis Foundation estimates that more than 400,000 people in the United States and about 2.5 million people around the world have MS. About 200 new cases are diagnosed each week in the United States. It is an expensive disease to treat, and the direct and indirect health care costs range from $8,528 to $54,244 per patient per year in the United States.
Multiple sclerosis disrupts the ability of parts of the nervous system to communicate, resulting in a range of physical, mental, and sometimes psychiatric problems. There is no known cure for MS, but current treatments attempt to improve function after an attack and prevent new attacks. Most medications used to treat MS may be effective in relapsing-remitting forms of the disease, but generally are ineffective in progressive forms that are characterized by a chronic demyelination of axons. Although, the immunomodulator ocrelizumab recently was shown to be effective in the progressive forms, ocrelizumab is associated with major potential side effects and poorly tolerated. See Montalban X. et al., “Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis,” New England Journal of Medicine 376 209-220 (2017).
In another approach, US 2013/0226133 describes a method of restoring the myelin sheath of nerve fibers using stephaglabrin sulfate. In another approach, US 2004/0141947 discloses a method for treating demyelinating CNS diseases using a colony stimulating factor or colony stimulating factor-like ligand such as sargramostim, a type 1 interferon-congener, and at least one additional therapeutic agent. In another approach, US 2004/0053850 describes a method of treating a demyelinating disease of the CNS by co-administering the tripeptide gly-pro-glu and an AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate)/kainate antagonist compound. In another approach, U.S. Pat. No. 4,760,092 claims a method of treating demyelinating diseases such as multiple sclerosis using colchicine or colchiceine. In another approach, US 2013/0302410 describes a method for neuroprotection in demyelinating diseases using dimethyl fumarate or monomethyl fumarate. In another approach, US 2013/0108643 describes a method of treating an autoimmune or inflammatory disease using an inhibitor of macrophage scavenger receptor class 1 MSR1. In another approach, EP 0423943 describes the use of an inhibitor of a member of the mammalian collagenase family of enzymes to treat demyelinating diseases.
Despite these proposed approaches, there remains a need for methods of promoting remyelination in subjects suffering from demyelinating diseases, such as MS.